Hemocompatible coatings on hydrophobic porous polymers

ABSTRACT

The present invention relates to coating a porous, hydrophobic polymer with a hemocompatible coating and to the materials produced thereby. One embodiment of the present invention relates to the coating of expanded poly(tetrafluoroethylene) with one or more complexes of heparin, typically containing heparin in combination with a hydrophobic counter ion. The hemocompatible coating is dissolved in a mixture of solvents in which a first solvent wets the polymer to be coated and the second solvent enhances the solubility of the hemocompatible coating material in the solvent mixture. Typical first solvents wetting hydrophobic polymers include non-polar such as hydrocholorofluorocarbons. Typical second solvents include polar solvents such as organic alcohols and ketones. Azeotropic mixtures of the second solvent in the first solvent are used in some embodiments of the present invention although second solvents may be employed in a range of concentration ranges from less than 0.1% up to saturation. An example is provided of coating heparin complex onto an endoluminal stent, typically consisting of coating DURAFLO onto an ePTFE stent covering material.

BACKGROUND

1. Field of the Invention

The present invention relates to the field of hemocompatible coatings onhydrophobic porous polymeric materials and, in particular, tohemocompatible coatings based upon complexes of heparin deposited uponporous hydrophobic polymers, typically expanded PTFE.

2. Description of Related Art

Continuing advances in medical technology have led to the developmentand use of numerous medical devices that come into contact with blood orother bodily fluids. To be concrete in our discussion, we focus hereinon the particular example of medical devices coming into contact withmammalian blood, particularly human blood, not intending thereby tolimit the scope of the present invention to medical devices usedexclusively on human patients. In using such devices, it is importantthat contact of the blood or other bodily fluid with the variouscomponents of the medical device not cause therapeutically detrimentalalterations to the fluid. In many cases, it is desirable to coat suchdevices with materials to enhance the biocompatiblity of the devices,including coatings that contain bioactive agents, anticoagulants,antimicrobial agents or a variety of other drugs.

It is convenient to consider blood-contacting medical devices asinvasive or extra-corporal, although some devices span both classes.Invasive devices are used internally in the treatment of the patient,implanted into the patient for an indefinite or extended period of timeor inserted into the patient for relatively brief periods. In manycases, the materials comprising the blood-contacting portions of theinvasive device lack sufficient biocompatibility and/orhemocompatibility, tending to cause changes harmful to the patient inthe blood or other fluid coming into contact with the surface (orsurfaces) of the device. In such cases it is desirable to coat thesurfaces of these devices with materials to enhance the biocompatiblityand/or hemocompatibility. Invasive devices that are typically coatedwith biocompatible or therapeutic substances include implantableartificial orthopedic devices, dental implants, intravascular catheters,emboli capturing systems, epicardial immobilization devices, grafts,stents, intraluminal prosthetic devices and artificial heart valves,among others.

There are also many examples of extra-corporal medical devices that comeinto contact with blood in which blood is transported and/or processedexternal to the patient. A few representative examples includecardiopulmonary bypass devices, kidney dialysis equipment, bloodoxygenators, separators and defoaming devices, among others. Followingsuch extra-corporal processing, the blood or other bodily fluid may bereintroduced into the patient, transported for storage and/or forintroduction into another patient. In using such extra-corporal devices,it is important that contact of the blood or other bodily fluid with thevarious components of the device not cause therapeutically detrimentalalterations to the fluid.

It is important in some cases that the surface or the surfaces of theinvasive or extra-corporal medical device be coated with substanceshaving therapeutic functions, wherein the coatings may serve severalfunctions in addition to increasing thebiocompatibility/hemocompatibility of the surface. Examples of suchadditional functions include the release of one or more therapeuticagents into the blood in appropriate dosages with appropriatetimed-released characteristics and at the proper location within thepatient. Thus, the medical device may serve as a convenient deliveryplatform for the delivery of therapeutically beneficial drugs inaddition to its other functions.

One important application related to implantable devices arises inconnection with endoluminal stents, particularly as occurring inconnection with percutaneous transluminal angioplasty (“PCTA”).Following balloon angioplasty, the lumen of the just-expanded vessel maycontract due to several causes. An initial rebound of the walls of thevessel may occur following removal of the balloon. Further thrombosis orrestenosis of the blood vessel may occur over time following theangioplasty procedure. The result is often the necessity for anotherangioplasty procedure or surgical by-pass. Endoluminal stents have beenin use for several years in conjunction with a surgical procedureinserting a tube or stent into the vessel following the PCTA procedureto assist in retaining the desired intraluminal opening. A review of theprocedure may be found in Endoluminal Stenting by Ulrich Sigwart, Ed.(W. B. Saunders, 1996). A compendium of coronary stents is given inHandbook of Coronary Stents, 3^(rd) Ed. by P. W. Serruys and M. J BKutryk, Eds. (Martin Dunitz Ltd., 2000). However, even with stenting,occlusions frequently recur within the stent requiring further PCTA orby-pass surgery. Such restenosis following PCTA and the insertion of astent is sought to be prevented by the use of coated stents. Coatings onstents are often used for the delivery of anticoagulants or othermedication that assist in preventing thrombosis and restenosis.

Heparin is an anticoagulant drug composed of a highly sulfatedpolysaccharide, the principle constituent of which is aglycosaminoglycan. In combination with a protein cofactor, heparin actsas an antithrobin (among other medical effects as described, forexample, in Heparin-Binding Proteins, by H. E. Conrad (Academic Press,1998)). Heparin is an attractive additive to coat on the surface(s) ofblood-contacting devices in order to increase the hemocompatibility ofthe material and/or to release heparin or heparin complexes into theblood to combat thrombosis and restenosis.

The heparin molecule contains numerous hydrophilic groups includinghydroxyl, carboxyl, sulfate and sulfamino making underivatized heparindifficult to coat onto hydrophobic polymers. Thus, many types ofcomplexes of heparin with hydrophobic counter ions have been used inorder to increase the ability of the heparin-counter ion complex to bindto hydrophobic surfaces. Such counter ions are typically cationic tofacilitate binding with anionic heparin, and contain a hydrophobicregion to facilitate bonding with the hydrophobic polymer. Typicalheparin complexes include, but are not limited to, heparin complex withtypically large quaternary ammonium species such as benzylalkoniumgroups (typically introduced in the form of benzylalkonium chloride),tridodecylmethylammonium chloride (“TDMEC”), and the commercial heparincomplex offered by Baxter International under the tradename DURAFLO orDURAFLO II. Herein we denote as “heparin complex” any complex of heparinwith a hydrophobic counter ion, typically a relatively large counterion. Examples of heparin complexes are described in the following U.S.Patents (incorporated herein by reference): U.S. Pat. Nos. 4,654,327;4,871,357; 5,047,020; 5,069,899; 5,525,348; 5,541,167 and referencescited therein.

Considerable work has been done in developing coatings for applicationto various medical devices in which the coatings contain at least oneform of heparin or heparin complex. Combinations of heparin and heparincomplexes with other drugs, as well as various techniques for tailoringthe coating to provide desired drug-release characteristics have beenstudied. Examples of such work include that of Chen et. al.(incorporated herein by reference), published in J. Vascular Surgery,Vol 22, No. 3 pp. 237-247 (September 1995) and the following U.S.Patents (incorporated herein by reference): U.S. Pat. Nos. 4,118,485;4,678,468; 4,745,105; 4,745,107; 4,895,566; 5,013,717; 5,061,738;5,135,516; 5,322,659; 5,383,927; 5,417,969; 5,441,759; 5,865,814;5,876,433; 5,879,697; 5,993,890 as well as references cited in theforegoing patents and article.

Implantable medical devices often require some degree of porosity toenable blood to come into contact with underlying tissues, to increasethe surface area for delivery of therapeutic substances, or for otherpurposes. Therefore, porous polymers are widely used in medical devices.The advantages of porosity are not limited to implantable devices, andporous materials are used in extra-corporal devices as well as invasivemedical devices. However, the problem of coating with heparin isexacerbated if the hydrophobic polymer is also porous. In addition tobinding with the hydrophobic surface, the heparin complex must alsopenetrate into the interstices of the porous structure of the polymerand bind to all or substantially all of the polymer surface that comesinto contact with blood.

Fluorinated polymers are typically chemically unreactive, have lowsurface energy and are hydrophobic. Such properties are generallyfavorable for use in medical devices as described, for example by F. H.Silver and D. L. Christiansen in Biomaterials Science andBiocompatibility, (Springer-Verlag, 1999) p. 19.Poly(tetrafluoroethylene), PTFE, is a polymeric material with repeatingunits of (—CF₂CF₂—) having numerous commercial uses, including inblood-contacting devices, due in large part to its chemical inertnessand desirable physical properties. PTFE in the form of a film or solidhas low surface energy and, therefore, is a relatively difficult surfaceto coat (or “wet”). “Wetting” typically indicates the tendency of aliquid to spread and coat the surface onto which it is placed. Thespecific relationship between surface energy and the contact angle atthe interface between a drop and the surface (the “wetting”) is given instandard references including Physical Chemistry of Surfaces 6^(th) Ed.by A. W. Adams and A. P. Gast (John Wiley, 1997), p. 465 ff. A contactangle between the liquid and the surface greater than approximately 90°typically indicates a non-wetting liquid on that particular surface.

In many medical and non-medical commercial uses, it is desirable to havePTFE in the form of a porous film that retains adequate physicalstrength for the particular application while not substantiallyincreasing the cost of the material. Expanded PTFE (hereinafter “ePTFE”)is a form of PTFE that has been physically expanded along one or moredirections to create a porous form of PTFE having varying amounts ofporosity depending on several factors including the specific proceduresfor performing the mechanical expansion. The porous ePTFE thus createdis useful for the manufacture of several commercial products asillustrated (for example) by the work of Gore in U.S. Pat. Nos.3,953,566 and 4,187,390 and the work of House et. al. in U.S. Pat. No.6,048,484. Applications to stents include the work of Lewis et. al.(U.S. Pat. No. 5,993,489) and Bley et. al. (U.S. Pat. Nos. 5,674,241 and5,968,070). The chemical inactivity, and other properties of fluorinatedpolymers including PTFE and ePTFE, have made them attractive substancesfor use in many medical and blood-contacting devices. Representativeexamples include dental implant devices (Scantlebury et. al. U.S. Pat.No. 4,531,916), grafts, stents and intraluminal prosthetic devices (Bleyet. al. U.S. Pat. Nos. 5,674,241 and 5,968,070; Goldfarb et. al. U.S.Pat. No. 5,955,016; Lewis et. al. U.S. Pat. No. 5,993,489; Tu et. al.U.S. Pat. No. 6,090,134).

Expanded PTFE is widely used in medical devices and is perhaps one ofthe most widely used vascular graft materials. In fact, ePTFE has alarge range of application in blood-contacting medical devicesincluding, but not limited to, segmental venous replacements,reconstructed veins in organ transplantation, polymer catheters,in-dwelling catheters, urological and coronary stents, covered stents,heart valves, dental implants, orthopedic devices, vascular grafts,synthetic by-pass grafts and other invasive and implantable medicaldevices. In addition, ePTFE can be used in extra-corporalblood-contacting devices. Examples include, but are not limited to,heart by-pass devices, kidney dialysis equipment, blood oxygenators,defoaming machines, among others.

FIG. 1 is a scanning electron micrograph of porous ePTFE from the workof House et. al. (U.S. Pat. No. 6,048,484). FIGS. 2A and 2B areschematic depictions of two forms of ePTFE showing biaxially orientedfibrils (FIG. 2A), and multiaxially oriented fibrils (FIG. 2B). BothFIGS. 2A and 2B are from House et. al. (supra). Low surface energycharacteristic of fluoropolymers and other hydrophobic polymers, incombination with the porosity of ePTFE, make the application of acoating to ePTFE, including coating of the interior surfaces of thepores, a significant challenge. Providing such a coating for ePTFE isone objective of the present invention.

However, when used in a blood-contacting environment, ePTFE tends to bethrombogenic and its porosity may release entrapped gases (which mayitself be a source of throbogenicity as discussed, for example, by Varinet. al U.S. Pat. No. 5,181,903). Therefore, considerable effort has goneinto the coating of ePTFE to reduce its throbogenicity and/or provideother therapeutic effects. Hemocompatibility can be achieved by avariety of means, including coating with a hydrophilic, biologicallypassive, polymer, or by coating with materials having a biologicallyactive component such as heparin or a complex of heparin including thecommercially available heparin complex DURAFLO or DURAFLO II (BaxterHealthcare, Inc.). Improved procedures for coating ePTFE withhemocompatible substances, typically substances containing derivativesor complexes of heparin, and the improved hemocompatible materials soproduced are among the objects of the present invention. We use theexpressions “derivative of heparin” and “complex of heparin”interchangeably herein without distinction to indicate a chemicalcombination of heparin with a counter ion.

Although fluoropolymers have been among the most commonly used materialsfor blood-contacting devices, polyurethanes, polyethylene terephthalates(“PETs”) and numerous other fluorinated and non-fluorinated polymershave also found considerable application. Modifications ofpolyurethanes, PETs and other plastics have included the introduction ofcoatings for antithrombogenic and anticoagulant properties. PET is anexample of a non-fluorinated polymer that is highly hydrophobic andtherefore difficult to coat with polar, aqueous materials such asheparin. PTFE is but one example of the general chemical class offluoropolymer that also includes FEP (fluorinated ethylene propylene),PFA (perfluoroalkyl vinyl ether and tetrafluoroethylene co-polymer),PVDF (polyvinylidenedifluoride), PVF (polyvinylfluoride), PCTFE(polychlorotrifluoroethylene), ETFE (ethylene and tetrafluoroethyleneco-polymer) TFB (terpolymer of vinylidenedifluoride, hexafluoropropyleneand tetrafluoroethylene) and other fluoropolymers as known in the artand described in many references including, for example, W. Woebcken inSaechtling International Plastics Handbook for the Technologist,Engineer and User, 3^(rd) Ed., (Hanser Publishers, 1995) pp. 234-240,incorporated herein by reference.

Coating the interior regions of highly porous materials such as ePTFEwith significant amounts of a hemocompatible coatings presents specialchallenges in addition to the hydrophobicity, deriving in part from therelative inaccessibility of much of the surface to be coated.

SUMMARY

The present invention relates to methods of coating porous, hydrophobicpolymers with a hemocompatible coating, to the materials producedthereby and to medical devices in which at least a portion of theblood-contacting surfaces thereof comprise such hemocompatiblematerials. One embodiment of the present invention relates to thecoating of expanded poly(tetrafluoroethylene), ePTFE, with one or morecomplexes containing heparin bonded to a hydrophobic counter ion. Theporous nature of ePTFE makes penetration and coating of the interiorregions of the material difficult due to surface tension effects,entrapped gases and similar phenomena characteristic of liquidpenetration into porous structures. Such porosity-related challenges tocoating are exacerbated by the low surface energy of PTFE. The presentinvention makes use of a solvent that both penetrates the porous regionsof ePTFE and dissolves heparin complexes. Solvents used pursuant to thepresent invention include non-polar solvents that wet PTFE.

A hemocompatible coating is dissolved in a mixture of solvents in whicha first solvent wets the polymer to be coated and the second solventenhances the solubility of the hemocompatible coating material in thesolvent mixture. First solvents that have the property of wettinghydrophobic polymers are typically non-polar. Typical second solventsinclude polar solvents such as organic alcohols, ketones, among otherpossibilities. In one embodiment, azeotropic mixtures of the secondsolvent in the first solvent are used, although concentrations of thesecond solvent from near zero up to saturation may be used. The presentinvention also relates to medical devices, including endoluminal stents,that employ the coated materials of the present invention. Producing aporous material having a hemocompatible coating on at least someblood-contacting surfaces thereof is a primary object of the presentinvention. Medical devices using such materials in a blood-contactingenvironment have the advantages of reducing the accumulation plateletsand thrombus on the coated surfaces.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Scanning electron micrograph of ePTFE from U.S. Pat. No.6,048,484.

FIG. 2A: Schematic depiction of porous structure of ePTFE from U.S. Pat.No. 6,048,484 depicting biaxially oriented fibrils.

FIG. 2B: Schematic depiction of porous structure of ePTFE from U.S. Pat.No. 6,048,484 depicting multiaxially oriented fibrils.

FIG. 3: Cut-away depiction of a portion of a covered stent.

DETAILED DESCRIPTION

The present invention relates to the coating of porous, hydrophobicpolymers, typically fluoropolymers such as expandedpoly(tetrafluoroethylene), ePTFE, with hemocompatible coatings, so as toperfuse and coat substantially all regions of the surface that come intocontact with blood, including the interior regions of the porousstructure that are difficult to access and difficult to coat byconventional means. Complexes of heparin are the typical hemocompatiblecoatings employed in some embodiments of the present invention.

We follow the conventional usage that “wetting” indicates that thecontact angle formed by the tangent to the surface of the liquid and thesurface of the solid at the point of contact is less than 90° (measuredthrough the liquid phase) such that the liquid tends to spread over thesurface of the solid. Conversely, nonwetting indicates that the liquidtends to ball up on the surface of the solid and run off the surfaceeasily. Contact angles are known in the art and provide one criteria bywhich candidate solvents of the present invention can be identified. Forexample, contact angles of selected liquids with selected surfaces(including fluoropolymers such as PTFE, FEP) are provided in PhysicalChemistry of Surfaces 6^(th) Ed. (supra) pp. 365-366.

The present invention is not inherently limited to ePTFE or tofluoropolymers as a class. Porous hydrophobic polymeric materials, thatare typically difficult to coat with hemocompatible materials byprocedures of the prior art are included within the scope of the presentinvention. Examples of porous hydrophobic polymers include thefollowing: porous polyethylene, porous polypropylene, porouspolyurethanes, porous polyacrylates, porous polymethacrylates, amongothers. Biocompatible polyurethanes, PETs and other polymers have alsobeen used as blood-contacting substances in medical devices, subject tocoating with heparin complexes and/or other hemocompatible ortherapeutic molecules pursuant to the methods of the present invention.However, PTFE is but one example of a class of commercially importantfluoropolymers. Other examples include those noted above; FEP, PFA,PVDF, PVF, PCTFE, ETFE, TFB and other fluoropolymers as known in theart. Blends containing ePTFE, other fluoropolymers and/or otherhydrophobic polymers are included within the scope of the presentinvention. Such blends are coatable by means of the procedures describedherein and the resulting coated materials useful in blood-contactingmedical devices.

To be concrete in our discussions we describe in detail the particularembodiments in which expanded PTFE is coated with a hemocompatiblecoating containing heparin as one component thereof. Other embodimentsmaking use of other porous hydrophobic polymers and/or otherhemocompatible coatings consistent with the procedures and conditions ofthe present invention represent obvious modifications of the presentinvention and are included within its scope.

The present invention relates to coating ePTFE without distinction as tothe particular microstructure present in the ePTFE prior to coating.Herein we use “ePTFE” to indicate any porous structure of the PTFEpolymer, irrespective of its specific and detailed microstructure andirrespective of the detailed procedure for its formation. Commerciallyavailable embodiments of ePTFE such as GORE-TEX (W. L. Gore andAssociates) are included. In some embodiments of the present invention,mechanically expansion of PTFE is the means by which porosity isobtained. However, as described by Gore (U.S. Pat. Nos. 3,953,566 and4,187,390, incorporated herein by reference), mechanical expansion isnot the only way to obtain porous PTFE. The coating procedures of thepresent invention can be used for coating porous polymeric materials,including ePTFE, irrespective of the specific mechanism by which theporosity is introduced into the material. However, for economy oflanguage, we use “ePTFE” to denote a porous form of PTFE, howeverproduced, recognizing that mechanically expanded PTFE is but one meansof obtaining the desired porosity.

Liquids having contact angles with PTFE less than 90° include non-polarorganic solvents such as alkanes (pentane, hexane, heptane and octane,among others) and cycloalkanes, freons or related materials such aschlorofluorocarbons (“CFCs”) and hydrochlorofluorocarbons (“HCFCs”).Commercial solvents include CFCs and HCFCs such as “Techspray AMS FluxRemover” (from Techspray, Inc., of Amarillo, Tex.) and “Gensolv 2004”(from Micro Care Corp. of Bristol, Conn.). Various ethers,tetrahydrofuran, dioxane are among the solvents wetting PTFE. For someembodiments of the present invention, a candidate solvent is any solventthat is known to wet fluoropolymers (particularly ePTFE) or thehydrophobic polymer of interest. Although pure solvents are discussedherein, this is merely for economy of language. Mixtures of solventsthat retain the property of being able to wet the hydrophobic surface,particularly ePTFE, are included within the scope of the presentinvention.

A hydrophobic complex of heparin is dissolved in the polymer-wettingprimary solvent for penetration into the porous structure and depositiononto ePTFE in some embodiments of the present invention. Some (typicallysmall) amount of heparin complex dissolves in pure polymer-wettingsolvent as described above, but typically does not lead to biologicallyuseful amounts of heparin being deposited onto the hydrophobic surfaces.Therefore, in some embodiments of the present invention, the solubilityof heparin complexes is enhanced by the addition of relatively smallamounts of a polar solvent to the non-polar primary solvent. Thenon-polar primary solvent is chosen to provide adequate penetration intothe interior of the porous hydrophobic material, while the polarsolubility-enhancing component of the solvent is selected to facilitatedissolution of heparin complexes in the solvent mixture. Candidate polarsolubility-enhancing additives included organic alcohols (methanol,ethanol, among others), ketones (acetone, methylethylketone, amongothers). Mixtures of one or more chemical compounds can also be used asthe solubility-enhancing solvent.

It is desirable, but not inherently necessary in some embodiments of thepresent invention, that the polar solvent be added to the non-polarsolvent in an amount so as to form an azeotropic mixture. Azeotropicmixtures have the property of evaporating such that the unevaporatedliquid retains the same composition to dryness. In contrast,non-azeotropic mixtures typically become more concentrated in the lessvolatile solvent as evaporation proceeds. A solute will thus experiencea changing solvent composition during evaporation for non-azeotropicmixtures. This may lead to precipitation of the solute and tend tocreate non-uniform coatings. Thus, while non-azeotropic mixtures may beused with acceptable results, azeotropic mixtures typically give bettercoatings.

One example of a substantially azeotropic mixture described in detailbelow includes a polymer-wetting solvent HCFC-225 containing about 6%methanol (by volume). This solvent mixture is found to be adequate insome embodiments of the present invention. “HCFC-225” is a mixture ofisomers of dichloropentafluoropropane, typically HCFC-225ca isCF₃CF₂CHCJ₂ and HCFC-225cb is CCIF₂CF₂CHFCl. However, azeotropicmixtures are not necessary in the present invention and adequate resultsare obtained with concentrations of polar solvent from approximately0.00001% up to saturation of the polar solvent dissolved in thenon-polar solvent. In some embodiments of the present invention,concentrations of polar solvent in the range from about 0.1% to about10% by volume are used. However, while the above ranges givetherapeutically useful amounts of hemocompatible coatings, betterquality coatings are typically obtained with concentrations in the rangefrom approximately 0.1% to approximately 2%. A range from approximately0.5% to approximately 1% is particularly useful in that 0.5% has enoughhemocompatible material for therapeutically effective coatings but 1% isdilute enough to avoid webbing.

Thus, the present invention includes adding relatively small amounts ofan organic alcohol (such as ethanol, methanol, among others) or asimilar solubility-enhancing polar solvent to a polymer-wetting solvent.The solubility enhancing solvent is added to the polymer-wetting solventin such quantity (typically small) that the mixed solvent providesadequate solubility for heparin complexes without substantiallyhindering penetration of the pores or wetting of the hydrophobicpolymer. Thus, in one embodiment a mixed solvent is created that bothwets ePTFE and delivers heparin to all surfaces of the porous structure.

Having dissolved a suitable heparin complex in a mixed solvent asdescribed herein, coating of the ePTFE with the heparin complex may beperformed by any convenient method that brings the heparin-containingsolution into intimate contact with all surface regions of the ePTFEsubstrate including the interior regions of the pores. Dip coating isone technique that can be used in some embodiments of the presentinvention although other coating techniques known in the art may also beused, including spraying.

FIG. 3 depicts a portion of an endoluminal stent in cut-away view,showing the interior region of the stent, 1, the struts, 2, and acovering, 3. The covering material for the stent, 3, is typically porousto allow blood flowing on the interior of the stent, 1, to come intocontact with the interior surfaces of the lumen in which the stent isplaced. Porous materials containing hemocompatible coatings thereon maybe used in many medical devices, one example of which is stent covering,3. Expanded PTFE is a typical stent covering material. Other materialsfor covering stents are described elsewhere herein and in the referencescited.

Hemocompatible coatings placed onto stent cover, 3, include heparin andheparin complexes. One embodiment of the present invention relates tocoating a ePTFE stent covering material with a heparin complex,typically DURAFLO or DURAFLO II. Typical pore sizes of ePTFE are in therange of approximately 5μm (microns) to approximately 200μm, commonly inthe range from approximately 40 μm to approximately 120 μm.

EXAMPLES

DURAFLO II may be used herein in place of DURAFLO without modification.

1) Prepare a solution consisting of the hydrochlorofluorocarbon HCFC-225and 6% by volume methanol whereby the methanol enhances the solubilityof the heparin complex in the HCFC solvent.

2) Dissolve in the solution of step 1, a heparin complex, DURAFLO. Theconcentration of DURAFLO in the solution is selected to provide thedesired coating of DURAFLO on the stent cover. Too little drug on thestent cover may be therapeutically ineffective. Too much may causeexcess amounts of drug to be released into the blood soon after thestent is implanted, to the detriment of the patient.

3) Dip ePTFE into the solution of step 2 allowing the solution toperfuse throughout the ePTFE porosity and deposit the DURAFLOthroughout.

4) Repeat step 3 if additional coating of DURAFLO is desired. Othersolvents that may be used in step 1 above include the following:

1-a) Techspray AMS Flux Remover containing approximately 6% methanol.

1-b) Genesolv 2004, dichlorofluoroethane containing approximately 4%methanol.

1-c) Cyclohexane including approximately 5% n-propanol. Other solutesthat may be used in step 2 above include the following:

2-a) TDMEC heparin.

2-b) Benzalkonium heparin. Concentrations of solute in solvent may beany convenient value leading to the appropriate deposition ofhemocompatible substance onto the surface of the polymer. Typicalconcentrations in the range of approximately 1%-3% are found to giveadequate coatings.

The material produced by the above procedure is a suitable stentcovering material containing DURAFLO (or other heparin complex) coatedon substantially all surfaces thereof that will be exposed to bloodduring use. Dip or spray coating is conveniently done on a porous,hydrophobic polymer already mounted on the struts, forming thereby astent covering. However, the hydrophobic, porous material may be coatedpursuant to the present invention before, during or following thefabrication of the material into a medical device. The timing of coatingand device fabrication is determined in part by manufacturingconsiderations including the damage likely to result to thehemocompatible coating by processing during device fabrication.

The properties of the coating can be tested in vitro by standard testingmethods including AT-III binding or anti-Factor Xa Assay. Otherbiological assays include various ex vivo shunts.

Having described the invention in detail, those skilled in the art willappreciate that, given the present disclosure, modifications may be madeto the invention without departing from the spirit of the inventiveconcept described herein. Therefore, it is not intended that the scopeof the invention be limited to the specific embodiments illustrated anddescribed.

We claim:
 1. A method of coating a blood-contacting porous hydrophobicpolymer component of a medical device with a hemocompatible substance,the method comprising: a) preparing a coating solution comprising amixture of: i) a first solvent that wets the porous hydrophobic polymer;ii) a second solvent that enhances the solubility of the hemocompatiblecoating substance in the coating solution; and iii) the hemocompatiblecoating substance; and b) depositing the hemocompatible coatingsubstance onto the porous hydrophobic polymer by contacting the polymerwith the coating solution, wherein the second solvent has aconcentration of 0.00001%-10% by volume.
 2. A method as in claim 1wherein sail second solvent is dissolved in said first solvent in suchquantity as to form an azeotropic mixture.
 3. A method as in claim 1wherein said medical device is a stent.
 4. A method as in claim 1wherein said porous hydrophobic polymer includes at least one polymerselected from the group consisting of porous polyethylene, porouspolypropylene, porous polyurethanes, porous polyacrylates, porouspolymethacrylates and porous fluoropolymers.
 5. A method as in claim 4wherein said porous fluoropolymer is expanded poly(tetrafluoroethylene).6. A method as in claim 1 wherein said first solvent is selected fromthe group consisting of tetrahydrofuran, dioxane, fluoropolymer-wettingalkanes, fluoropolymer-wetting cycloalkanes, fluoropolymer-wettingethers, fluoropolymer-wetting chlorofluorocarbons, fluoropolymer-wettinghydrofluorocarbons and mixtures thereof.
 7. A method as in claim 1wherein said hemocompatible coating substance comprises a complex ofheparin with a hydrophobic counter ion.
 8. A method as in claim 7wherein said hydrophobic counter ion is a hydrophobic quaternaryammonium ion.
 9. A method as in claim 7 wherein said hydrophobic counterion is selected from the group consisting of benzylalkonium ion andtridodecylmethylammonium ion.
 10. A method as in claim 1 wherein saidsecond solvent is selected from the group consisting of organicalcohols, ketones, and mixtures thereof.
 11. A method as in claim 1wherein said second solvent is dissolved in said first solvent in amountfrom about 0.1 volume percent to about 10 volume percent.
 12. A methodas in claim 1 wherein said second solvent is dissolved in said firstsolvent in amount from about 0.1 volume percent to about 2 volumepercent.
 13. A method as in claim 1 wherein said second solvent isdissolved in said first solvent in amount from about 0.5 volume percentto about 1 volume percent.
 14. A method as in claim 1 wherein said firstsolvent is a mixture of isomers of dichloropentafluoropropane and saidsecond solvent is methanol dissolved in said first solvent so as to forma volume percent solution.
 15. A method as in claim 1 wherein said firstsolvent is cyclohexane and said second solvent is n-propanol dissolvedin said first solvent to form a 5 volume percent solution.
 16. A methodas in claim 1 wherein said hydrophobic polymer is coated with saidhemocompatible coating substance by dip coating or spray coating. 17.The method of claim 1 wherein the first solvent is ahydrochlorofluorocarbon HCFC-225, dichlorodifluoroethane, orcyclohexane.
 18. The method of claim 17 wherein the second solvent inmethanol, n-propanol, acetone, methylethylketone, or ethanol.
 19. Themethod of claim 18 wherein the hemocompatible coating substance is aheparin salt with a quaternary ammonium cation.